Methods

We enrolled 46 consecutive patients, followed at our ambulatory clinic for angina with normal coronary arteries, who fulfilled the following inclusion criteria: (1) a diagnosis of stable primary MVA based on the presence of (i) a history of typical effort angina, (ii) exercise-induced ST-segment depression ≥1 mm, (iii) normal coronary angiography, (iv) absence of any specific cardiac disease including vasospastic angina, (v) normal echocardiographic examination including absence of left ventricular hypertrophy, and (vi) a coronary flow reserve <2.5 in the left anterior descending coronary artery as assessed by coronary blood flow (CBF) response to adenosine at transthoracic Doppler echocardiography , (2) suboptimal control of symptoms on conventional anti-ischemic therapy, as indicated by the occurrence of ≥1 episode per week of angina, (3) no previous consumption of the drugs under investigation, and (4) no apparent contraindications to ivabradine and ranolazine administration.

After baseline assessment, patients were randomized, according to a computer-generated table of random numbers, to receive 1 of the following drug regimens for a period of 4 weeks: (1) ivabradine, 5 mg twice daily, (2) ranolazine, 375 mg twice daily, or (3) placebo twice daily. Drugs were given to patients in anonymous drug packages by three of the authors (AV, ADF, PT) who were not involved in the clinical assessment of patients. Cardiologists involved in the clinical and laboratory assessment of patients and/or analyses of data were blinded to the allocation treatment.

After 1 week of treatment, patients underwent a clinical visit and a 12-lead electrocardiogram (ECG) to assess tolerability of therapy and exclude side effects. We chose to assess the effects of the lowest dose only of the 2 drugs in this study for 2 reasons: (1) to minimize possible side effects deriving from the addition of new drugs in patients already taking several medications and (2) to avoid differences in the management of the drugs; indeed, although a reference parameter to adjust the dose of ivabradine (i.e., a heart rate at rest <60 beats/min) exists, an analogous parameter does not exist for ranolazine.

The study complies with the Declaration of Helsinki and was approved by the local ethics committee of our institutes. All subjects were informed of the purpose and nature of the study and provided written, informed consent for participation.

The primary end points of the study were anginal status and quality of life (QoL). Anginal status was assessed by the Seattle Angina Questionnaire (SAQ). Each SAQ item (physical limitation, angina frequency, angina stability, treatment satisfaction, disease perception) is scored on a 0 to 100 scale, with higher scores indicating better functional status. QoL was assessed by the validated EuroQoL visual analogic scale (VAS), from 0 (worst condition) to 100 (best condition).

The following tests were performed both at baseline and at follow-up: (1) maximal symptom/sign-limited exercise stress test (EST), (2) CBF response to adenosine and to cold pressor test (CPT), and (3) peripheral flow-mediated dilation (FMD) and nitrate-mediated dilation (NMD).

ESTs were performed in the morning, in a fasting state, according to a standard symptom/sign-limited Bruce protocol. Leads II, V2, and V5 were monitored continuously. A 12-lead ECG was printed and blood pressure was measured at baseline, the end of each stage, at peak EST when clinically indicated, and at 1-minute intervals in the recovery phase. EST was stopped in cases of physical exhaustion, progressive angina (Borg scale >6) or relevant clinical events (e.g., dyspnea, hypotension, arrhythmias). ST-segment depression was considered significant if it was horizontal or downsloping and >1 mm at 0.08 seconds from the J-point in at least 3 consecutive beats in any lead but aVR. If EST was negative, in statistical analyses time, heart rate and blood pressure at 1 mm ST-segment depression and at angina were considered those recorded at peak EST.

Coronary microvascular dilator function was assessed noninvasively by measuring the increase in CBF in response to an endothelium-independent (adenosine) and to an endothelium-dependent (CPT) stimulus using transthoracic Doppler echocardiography. The tests were performed in the early afternoon, in a fasting state, following methods described in detail elsewhere. Briefly, in each patient, the left anterior descending coronary artery was imaged by a 7-MHz transducer connected to an Acuson Sequoia C512 ultrasound system (Siemens SpA, Milano, Italy), and diastolic CBF velocity was recorded by pulsed-wave Doppler signal both at rest and at peak infusion of adenosine (140 μg/kg/min) EV for 90 seconds, under ECG and blood pressure monitoring. After 15 minutes from recovering basal values of heart rate and blood pressure, CBF velocity was again recorded at rest and at peak CPT, performed by putting the patient’s left hand in ice water for 120 seconds. Coronary microvascular dilation in response to adenosine and CPT was measured as the ratio of CBF velocity at peak of each test to the respective basal value.

Systemic endothelium–dependent vasodilation was assessed by measuring FMD, following methods described in detail elsewhere. Shortly, after a 10-minute rest, images of the right brachial artery were obtained by a 10-MHz probe attached to a high-resolution ultrasound machine. A mechanical support maintained the probe in a fixed position throughout the examination. Brachial artery diameter was measured throughout the test using a totally automated system, which provides a diameter measurement every second. After obtaining basal measures, a forearm cuff, positioned 1 cm under the antecubital fossa, was inflated to 250 mm Hg and released after 5 minutes to elicit forearm reactive hyperaemia. FMD was calculated as the maximum percent change of the brachial artery diameter during hyperaemia compared with the basal diameter.

After 15 minutes from recovery of brachial artery diameter to basal values, NMD was assessed. To this aim, 25 μg of sublingual glyceryl trinitrate was given, and NMD was measured as the maximum percent change in the next 5 minutes of the brachial artery diameter compared with the basal diameter.

We calculated that 15 patients per group was sufficient to attain a statistical power >90% to detect as significant (at p <0.05) a difference of 15 points (with a standard deviation of 10) between each active drug versus placebo in any SAQ item and in the EuroQoL score.

All variables considered in our study showed a distribution that was not different from the normal one according to Kolmogorov-Smirnov test. Comparisons among groups of continuous variables were done by analysis of variance (ANOVA), whereas categorical variables were compared by chi-squared test. Two-way repeated-measure ANOVA was performed to compare the effects of the different treatments on the outcome variables. In cases of global statistical significance, between- and within-groups comparisons were done by unpaired and paired t test, respectively, with statistical results of multiple comparisons corrected by Bonferroni rule. Statistically significant results were also adjusted for basal clinical variables. SAQ items and VAS score at follow-up in the 3 groups were also directly compared by ANOVA with adjustment for basal values. Data are reported as mean ± SD or proportions. A 2-tailed p value <0.05 was considered statistically significant. Data were analyzed by the SPSS 17.0 statistical software (SPSS Italia, Florence, Italy).

Results

Table 1 shows the main clinical characteristics of the 3 groups. There were no differences among groups with regard to age, gender, cardiovascular risk factors and drug therapy. Heart rate at rest was also comparable in the 3 groups (ivabradine 72 ± 5 beats/min; ranolazine 69 ± 5 beats/min; placebo 71 ± 6 beats/min; p = 0.21). At 1-week follow-up, heart rate at rest was reduced in the ivabradine group, whereas it was unchanged in the ranolazine and placebo groups (58 ± 3, 68 ± 6, and 67 ± 6 beats/min, respectively; p <0.001). No patient complained of side effects related to the treatment.

SAQ scores and EuroQoL VAS data are summarized in Table 2 . Basal values were similar in the 3 groups. A significant difference among groups in the changes from baseline to follow-up was found for all scores (p <0.01), even after correction for basal values. SAQ items and EuroQoL VAS improved significantly in both ivabradine and ranolazine groups, whereas no changes were observed in group placebo. Comparisons of ivabradine and ranolazine groups showed that ranolazine achieved better results for several SAQ items and for the EuroQoL VAS ( Table 2 , Figure 1 ).

Results of the SAQ and EuroQoL scale at baseline and follow-up in the groups of patients treated by ivabradine or ranolazine. p values refer to comparisons of changes between the ivabradine group and the ranolazine group at follow-up compared with baseline, as derived by variable-group interaction analyses on repeated-measure ANOVA. Data are means ± SEM.

The main EST results are summarized in Table 3 . There were no differences among groups in EST parameters at enrolment. At baseline, all patients developed ST-segment depression ≥1 mm during EST, whereas angina was reported by only 5, 7, and 5 patients in the placebo, ivabradine, and ranolazine groups, respectively. At follow-up, heart rate at peak EST was significantly reduced in the ivabradine group, whereas no significant changes were reported in the other 2 groups.

Table 3

Exercise stress test results at baseline and at follow-up in the 3 groups of study

	Ivabradine		Ranolazine		Placebo		p
	Baseline	Follow-up	Baseline	Follow-up	Baseline	Follow-up
1 mm STD
HR (beats/min)	115 ± 23	115 ± 15	116 ± 19	127 ± 15	125 ± 24	122 ± 20	0.12
SBP (mm Hg)	158 ± 26	159 ± 28	153 ± 17	156 ± 15	160 ± 22	161 ± 25	0.93
RPP (beats/min × mm Hg)	18,334 ± 5,353	18,401 ± 4,189	17,767 ± 3,357	19,906 ± 3,604	20,191 ± 5,747	19,957 ± 5,699	0.27
Time to 1 mm STD (s)	262 ± 103	337 ± 157	299 ± 127	407 ± 149 †	282 ± 131	285 ± 135	0.03
Peak exercise
HR (beats/min)	135 ± 17	121 ± 14 ∗	129 ± 17	131 ± 15	141 ± 20	136 ± 17	0.004
SBP (mm Hg)	177 ± 29	166 ± 28	163 ± 21	160 ± 14	183 ± 29	179 ± 31	0.70
RPP (beats/min × mm Hg)	23,828 ± 4,645	20,194 ± 3,985	21,083 ± 4,103	21,164 ± 3,525	25,583 ± 5,223	24,502 ± 5,721	0.07
Time (s)	376 ± 128	402 ± 137	401 ± 139	450 ± 126 †	420 ± 145	403 ± 128	0.03
Maximal STD (mm)	1.3 ± 0.4	0.8 ± 0.6	1.2 ± 0.5	0.6 ± 0.6	1.4 ± 0.4	1.3 ± 0.4	0.06

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